• Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA.
• Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
• Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
• Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA.
• Section on Cardiology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
• Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan.
• Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
• Broad Institute of Harvard and Massachusetts Institute of Technology and Cardiovascular Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
• Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
• Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, China.

BACKGROUND: Choline is an essential nutrient; however, the associations of choline and its related metabolites with cardiometabolic risk remain unclear.

OBJECTIVE: We examined the associations of circulating choline, betaine, carnitine, and dimethylglycine (DMG) with cardiometabolic biomarkers and their potential dietary and nondietary determinants.

METHODS: The cross-sectional analyses included 32,853 participants from 17 studies, who were free of cancer, cardiovascular diseases, chronic kidney diseases, and inflammatory bowel disease. In each study, metabolites and biomarkers were log-transformed and standardized by means and SDs, and linear regression coefficients (β) and 95% CIs were estimated with adjustments for potential confounders. Study-specific results were combined by random-effects meta-analyses. A false discovery rate <0.05 was considered significant.

RESULTS: We observed moderate positive associations of circulating choline, carnitine, and DMG with creatinine [β (95% CI): 0.136 (0.084, 0.188), 0.106 (0.045, 0.168), and 0.128 (0.087, 0.169), respectively, for each SD increase in biomarkers on the log scale], carnitine with triglycerides (β = 0.076; 95% CI: 0.042, 0.109), homocysteine (β = 0.064; 95% CI: 0.033, 0.095), and LDL cholesterol (β = 0.055; 95% CI: 0.013, 0.096), DMG with homocysteine (β = 0.068; 95% CI: 0.023, 0.114), insulin (β = 0.068; 95% CI: 0.043, 0.093), and IL-6 (β = 0.060; 95% CI: 0.027, 0.094), but moderate inverse associations of betaine with triglycerides (β = -0.146; 95% CI: -0.188, -0.104), insulin (β = -0.106; 95% CI: -0.130, -0.082), homocysteine (β = -0.097; 95% CI: -0.149, -0.045), and total cholesterol (β = -0.074; 95% CI: -0.102, -0.047). In the whole pooled population, no dietary factor was associated with circulating choline; red meat intake was associated with circulating carnitine [β = 0.092 (0.042, 0.142) for a 1 serving/d increase], whereas plant protein was associated with circulating betaine [β = 0.249 (0.110, 0.388) for a 5% energy increase]. Demographics, lifestyle, and metabolic disease history showed differential associations with these metabolites.

CONCLUSIONS: Circulating choline, carnitine, and DMG were associated with unfavorable cardiometabolic risk profiles, whereas circulating betaine was associated with a favorable cardiometabolic risk profile. Future prospective studies are needed to examine the associations of these metabolites with incident cardiovascular events.